Early wound healing occurs during a period of negative energy balance and negative bodily balance of most constituents. In addition, a continuously open wound impairs host protein anabolism and restoration of lost body composition. These findings suggest a biological priority of healing wounds and the transmission of a message from the wound to the host. Glucose, amino acid and energy metabolism are altered in wound tissue. These alterations in wound metabolism could be caused by 1) neural stimulation; 2) hormonal and substrate alterations following wounding; or 3) local changes in the wound. A perfused wound model, developed in our laboratory, has demonstrated characteristically altered wound metabolism occurs in the absence of hormones and with perfusate substrate concentrations which mimic the plasma of normal fed rats. These findings suggest that metabolic changes observed in wounded muscle are local and may proceed in the absence of the hormonal and substrate environment that follow wounding thus confirming biological priority. The relationship between this environment in response to wounding and convalescence, and the local changes in a healing wound will be explored using this isolated perfused rat hindlimb model. The hormone and substrate milieu, present in control animals and at various intervals following wounding, will be determined and reproduced in the perfusate. Since the wound model is denervated, this approach allows evaluation of the other non-local variable (i.e., the hormone and substrate milieu) on wound amino acid and glucose metabolism and on collagen synthesis. Wounded tissue has accelerated glycolysis with the concomitant production of many gluconeogenic substrates. We have shown glycolysis in wounded tissue to be aerobic suggesting impairment of shuttle mechanisms for oxidation of NADH. The involvement of these shuttle mechanisms will be evaluated. Since there is no obvious flux-generating step in wounded muscle for glycolysis, it is most likely this step is one of glucose production external to the wound. As a consequence, it is proposed to evaluate the effect of substrate supply from the wound and the hormonal milieu on glucose production in the liver. In addition, the effect of glucose supply on glycolysis and glucose disposal in the wound will be examined. The effect of exogenous amino acid supply on collagen synthesis in wounded tissue will be investigated. This is a comprehensive proposal which seeks to understand many of the important processes that bestow biological priority to healing wounds.